20-arylazo-5, 17(20)-pregnadien-3, 16alpha-diols and esters thereof



United States Patent ee 2,808,399

Fatented Oct. 1, 1957 1 2 i This reaction is conveniently carried out in an organic 2,808,399 solvent lacking a carbonyl group, such as a-low er alkanol. 20 0 5 17 20 3 1 As most arylhydi'azine condcnsations a catalytic amount A ESTERS T F of an acid such as an arylsulfonic acid facilitates thereit action. However, an excess of acid should be avoided vn M; D6650, Park R asslgnorilly meme for it-has been found that treatment of the 16,17-e'poXy assignments, to. G. 1); Searle & Co., Skokne, 11]., a t

pregnenolone or its B-ester of the foregoing type with corporatwn of ai' an arylhyd'razine in the presence of a larger am ou nt of No Drawing. Application December 1, 1954, a lower alkanoic acid such as acetic acid yields the aryl- Serial No. 472,519 1 hydrazone of a l'6 -alkanoyloxy-3,17a-hydroxypregnem Claims. 20-one or its 3-ester of the type CH: The present invention relates to a new group of 20- arylazosteroids and, more particularly, to the 20-arylazo- 15 OH I t 5,17()-pregnadien-3,16u diols and their esters and to a t the process for their preparation.

These compounds can be represented by the general structural formula CH3 n b N=N-Ar I I The present invention offers a useful procedure for the -OR' introduction of a 16u-hydroxy radical into steroids. Thus, treatment of a 20-ary1azo-5,l7-pregnadien-3,l6ot-diol or its ester of the type EH3 R0 CH8 I N N Ar wherein Ar is a member of the class consisting of aryl hydrocarbon radicals containing pr'ferably 6-9 carbon atoms and their halogenated derivatives and wherein R and R are members of the class consisting of hydrogen 5 and acyl radicals derived from hydrocarbon carboxylic acids containing preferably 18 carbon atoms.

In the foregoing structural formula Ar can be an aryl hydrocarbon radical such as phenyl, tolyl, xylyl, cumyl, wherein R d R trimethylphenyl, and the like. The radical Ar can also 4 an aryl, haloaryl 0 represent a halogenated derivative of such an aryl radical O are defined as hereinabove and Ar is r nitroaryl radical with acetic acid and aqueous pyruvic acid yields a 16a,17a-dihydroxysteroid such as a fluorophenyl, chlorophenyl, bromophenyl, iodoof the structural f l phenyl, chlorotolyl, bromoxylyl, or similar radical. The Cm radicals R and R can be hydrogen or acyl radicals de- CH: rived from such acids as formic acetic, propionic, butyric, 6 vale'ric, caproic, benzoic, toluic, phenylacetic, cyclohexane- CH3 carboxylic, cyclohexaneacetic, cyclopentanepropionic acid and the like. v I

The compounds of this invention are conveniently prepared by a condensation which can be represented as follows CH3 R0 OHa . i which has valuable hormonal and cardiovascular activity. 0H3 These compounds are described in detail in the copending application by Frank B. Colton, Serial No. 461,925, filed October .12,- 1954, which issued on December 20,

1955 as U. S. 2,727,909

Reduction of the phenylazo radical with zinc dust followed by hydrolysis of the phenylhydrazone under the R0 M NH NR2 above conditions yields 16u-hydro5rysteroids of the type CHa CH5 CH5 t OH; H N N Ar CH 00 fi-O'H OH I no I Besides being valuable intermediates in the organic synthesis of other hormonal and cardiovascular agents, the phenylazo compounds of this invention also have pharmaceutically valuable properties- Thus they produce a cortisone-like inhibition in such inflammatory conditions as allegeric iritis without, however, producing the undesirable side efliects of cortisone which limit its therapeutic applicability. They are also active antihypertensive agents.

The following examples illustrate in further detail the compounds which constitute this invention and methods for their preparation. However, they are not to be construed as limiting it in spirit or in scope. In these examples quantities of materials are indicated as parts by weight and temperatures in degrees centigrade.

Example 1 Under an atmosphere of nitrogen a mixture of 3 parts of 3-hydroxy-16,17-epoxy-5-pregnen-20-one, 3.3 parts of phenylhydrazine, 80 parts of methanol and 0.01 part of p-toluenesulfonic acid are stored at room temperature for 24 hours. The precipitate is collected on a filter and washed thoroughly with methanol. The orange colored 20+phenylazo-5', 17 (20) -pregnadien-3 3, 1 6a-di0l thus obtained melts at about 207209 C. It has the structural formula The ultraviolet absorption spectrum shows a maximum at about 315 millimicrons with a molecular extinction coefiicient of 23,200.

Example 2 A mixture of 1 part of 20-phenylazo-5,17(20)-pregnadien-3,16a-diol, 50 parts of pyridine and 20 parts of acetic anhydride is permitted to stand at room temperature for 15 hours and is then diluted with ice. The orange precipitate is collected on a filter and recrystallized from methanol. The 36,160: diacetoxy 20 phenylazo 5, l7(20)-pregnadiene thus obtained melts at about 206 207.5 C. The ultraviolet absorption spectrum shows a maximum at about 314 millimicrons with a molecular extinction coefiicient of 27,000. The compound has the structural formula CH! J)N=NC0H CH:

-O-COCHI CHI-COO Example 3 Under a nitrogen atmosphere a mixture of 3.4 parts of 3-acetoxy-l6,l7-epoxy-5-pregnen-20-one, 4.5 parts of 2,4,5-trimethylphenylhydrazine, 100 parts of methanol and 0.01 part of p-toluenesulfonic acid is maintained at 25 C. for 24 hours. The resulting precipitate is col- Example 4 A mixture of 1 part of 3-hydroxy-16,17-epoxy-5-pregnen--one and 1 part of 4-fluorophenylhydrazine in 30 parts of methanol is treated with 0.01 part of p-toluenesulfonic acid and then maintained at room temperature under a nitrogen atmosphere. The resulting precipitate is then collected on a filter and washed with methanol to yield the dark orange colored 20-(4-fiuorophenyl)azo- 5,l7(20)-pregnadien-3,l6a-diol. The infrared absorption spectrum shows maxirna at 2.90, 3.00, 6.12, and 7.30 microns. The compound has the structural formula Example 5 Condensation of 1 part of 4-chlorophenylhydrazine, 1 part of 3fl-hydroxy-16,l7-'epoxy-5-pregnen-20-one, 30 parts of methanol and 0.01 part of p-toluenesulfonic acid by the method of the preceding example yields the 20- (4-chlorophenyl) azo-5, 17 (20 -pregnadien-3, 160c-di0l in orange prisms. The infrared absorption spectrum shows maxima at 2.89, 3.00, 6.10, and 7.31 microns. The compound has the structural formula Example 6 A mixture of 7 parts of 3-acetoxy-16,17-epoxy-5-pregnen-ZO-one and 7 parts of 2-iodophenylhydrazine in 250 parts of methanol is treated with 0.02 part of p-toluencsulfonic acid and then permitted to stand under a nitrogen atmosphere at 25 C. for 24 hours after which the yellowish-orange precipitate is collected on a filter and washed with methanol. There is thus obtained the highmelting 3-acetoxy-20 2-iodophenyl) azo-5, l7-pregnadien- 16a-ol. The infrared absorption spectrum shows maxima 5 at 2.98. 5.77; 6113, 7.30,- and 8314 microns. The "com pound has the structural formula CH3 v b-N=N-- 0113 -OH l CHE-CO Example 7 To a solution of 2 parts of 20-pl1enylazo-5,17(20)- pregnadien-3,16u -diol in 100 parts of pyridine are added 4 parts of benzoyl chloride and the mixture is hiaifit'ained at 25 C. for 20 hours. The mixture is then diluted with ether, washed successively with water, 5% aqueous sodium hydroxide and again with Water, dried over anhydrous sodium sulfate, filtered and evaporated. The residue is washed with benzene. There is thus obtained 3,16 dibenzoyloxy 20 phenylazo 5,l7(20) pregnadiene which shows infrared maxima at 6.13 and 7.30

Example 8 Substitution of 4.5 parts of -cyciepeittanepropien 1 chloride for the benzeyi chloride used in the preceding example yields the 3,l6-bis(cyclopentanepropionylorky)- 20-phenylazo-5,l7-pregnadiene of the structural formula in shining yellowish orange crystals. The infrared absorption spectrum shows maxima at 5.78, 6.12, 6.86,"-7.30 and 8.10 microns.

Exam le 9 To a solution of 2.2 parts of 20 phehylazo'-5,l7 20)-- pregnadien-3,16a-diol in 105 parts of glacial acetic acid, there are added 2.2 parts of pyruvic acid in 50 parts of water and the mixture is permitted to stand at room temperature for 24 hours. It is then diluted with water and the precipitate is collected on a filter, dried and crystallized from acetone. The 3,8,16a,l7a-trihydroxy-5-pregnen-20-one thus obtained melts at about 224-225 C., resolidifies and melts again at about 244-247 C.

Example 10 A solution of 10 parts of ZO-phenylazo-S,17(20)-pregnadien-3,l6a-diol iii 200 parts of pyridine is stirred with 10 parts of zinc dust and 10 parts of glacial acetic acid for 10 minutes. The zinc dust is filtered from the solution; the reduced material is precipitated 'by the addition of water and separated by filtration.

A solution of 6 parts of the reduced material so obtained in 220 parts of glacial acetic acid is treated with parts of water and T0 parts of pyruvic acid. The mixture is shaken and within a few minutes the initial green color fades out. After 20 minutes of standing at room temperature a small precipitate is removed by filtration. The filtrate is allowed to stand at room temperature for 18 hours and thendiluted with water.- The resulting precipitatejjs collected on a filter and crystallized fromace tone. The 3/8,l6a-dihydroxy-S-pregnen-ZO-one thus,;obtained melts at about 232-235 C. Crystallization from dilute methanol raises the melting point to 241.5-244 C.

What is claimed is;

1. A compound of the structural formula 1 wherein Ar is a member 'of the class consistiii'g' of aryl hydrocarbon radicals containing 6-9 carbon atoms and halophenyl r'adicals and wherein R and R are members of the class consisting of hydrogen benzoyl and acyl radicals derived from alkanoic acids of les's than 9 carbon atoms.

2. A compound of the structural formula wherein Ar is an aryl hydrocarbon radical containing 6-9 carbon atoms.

3. A compound of the structural formula 4. A compound of the structural formula wherein Ar is an aryl hydrocarbon radical containing 6-9 carbon atoms and R and R are lower alkanoyl radicals.

5. A compound of the structural formula CN=N-CQH5 OH: I

0H.a-G O O 6. 3,16 dibenzoyloxy phenylazo 5,17(20)- pregnadiene.

7. A compound of the structural formula CH3 Halogen J-N=N OH: I

8. A compound of the structural formula CH3 Halogen C-N=N wherein R and R are lower alkanoyl radicals.

9. The process of preparing a compound of the structural formula CHa 8 wherein Ar is a member of the class consisting of aryl hydrocarbon radicals containing 6-9 carbon atoms and halophenyl radicals and wherein R is a member of the class consisting of hydrogen, benzoyl and acyl radicals derived from alkanoic acids of less than 9 carbon atoms which comprises mixing of a compound of the structural formula with an equivalent of an arylhydrazine of the structural formula 10. The process of preparing a compound of the structural formula CHI wherein Ar is a member of the class consisting of aryl hydrocarbon radicals containing 6-9 carbon atoms and halophenyl radicals and wherein R is a member of the class consisting of hydrogen, benzoyl and acyl radicals derived from alkanoic acids of less than 9 carbon atoms which comprises mixing of a compound of the structural formula with an equivalent of an arylhydrazine of the structural formula A1NH-NH2 in a lower alkanol solution.

No references cited. 

1. A COMPOUND OF THE STRUCTURAL FORMULA 